Palladium carbene reactions

Members of the tetracyclic dibenzopyrrocoline alkaloid family can be prepared by the intramolecular ring closure of l-(o-halobcnzyl)-tetrahydroisoquinoline derivatives. (3.38.)47 The analogous transformation of dihydroisoquinolines (3.39.) proceeds probably through the isomeric enamine form obtained by the tautomeric shift of the double bond 48 The palladium-carbene catalyst system applied in these reactions was also effective in the preparation of indoline, indolizidine and pyrrolizidine derivatives 49... 

Fig. 10. Multiple derivatization of purines including palladium-catalyzed reaction at the poorly reactive C2 position, (a) NaBH(OAc)3, 1% HOAc, THF (b) 59 (0.5 equiv.), 2,6-dichloropurine (1 equiv.), DIEA (1.5 equiv.), BuOH 80° (c) R2OH, PPh3, DiAD (1.5 2 1.3) in excess, THF, RT (d) boronic acids (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, Cs2C03 (6 equiv.), 1,4-dioxane, 90°, 12 h (e) anilines (5 equiv.), 7% Pd2(dba)3, 14% carbene ligand, KO Bu (6 equiv.), 1,4-dioxane, 90°, 12 h (f) phenols (5 equiv.), 7% Pd2(dba)3, 28% phosphine ligand, K3P04 (7 equiv.), toluene, 90°, 12 h (g) primary or secondary amines (5 equiv.), 90°, 12 h.

Type III reactions proceed by attack of a nucleophile at the central sp carbon of the allenyl system of the complexes 5. Reactions of soft carbon nucleophiles derived from active methylene compounds, such as /i-kcto esters or malonates, and oxygen nucleophiles belong to this type. The attack of the nucleophile generates the intermediates 9, which are regarded as the palladium-carbene complexes 10. The intermediates 9 pick up a proton from the active methylene compound and n-allylpalladium complexes 11 are formed, which undergo further reaction with the nucleophile, as expected, and hence the alkenes 12 are formed by the introduction of two nucleophiles. 

Abstract N-heterocyclic carbenes (NHCs) have attracted increasing attention since their discovery. Notably, they have allowed for major advances in palladium-catalyzed reactions. Mainly known for their application in cross-coupling reactions, this review intends to provide a broader overview of (NHC)-palladium systems in organic transformations. 

In spite of the successful use of NHCs in a number of palladium-catalyzed reactions, no system for hydrogenation was reported until 2005. This can be easily explained as it had been observed that hydridopalladium-carbene species decompose due to attack of the hydride on the carbene, which results in its reductive elimination to yield the corresponding imidazolium salt [ 190]. However, Cavell and co-workers recently showed that the oxidative addition of imidazolium salts to bis-carbenic palladium complexes leads to isolable NHC-hydridopalladium complexes [191]. This elegant work evidenced the remarkable stabilizing effect of NHC ligands in otherwise reactive species and led to the development of the first NHC-palladium catalyst for hydrogenation. 

C4Ciim][BF4] [QCpmJBr Pd(OAc)2 NaOAc 90-125 °C. Phosphine-free arylation of acrylates higher reaction rates in due to in situ formation of palladium carbene halides product extracted with ethyl acetate. [20]... 

Comparable reaction conditions were applied in the coupling of activated and non-activated arylchlorides with styrene or 2-ethylhexyl acrylate, using the palladium carbene catalysts shown in Scheme 6.6. While compounds 22 and 23 were found to be highly active catalysts, complex 21 was thermally unstable and decomposed to palladium black during the catalysis.1671 The yield and selectivity were only moderate in DMA, but results improved markedly when the reaction was carried out in [(C4)4N]Br. 

The same reaction was also investigated using the palladium-carbene complex, 58, as catalyst (Scheme 9.12).1401 Of the different ionic liquids studied, tetrabutylammonium bromide gave by far the best results while imidazolium based solvents afforded only poor conversions. At atmospheric pressure, only iodobenzene was carbonylated. The conversion of less reactive arylhalides not only required higher CO-pressures, but also the addition of a phosphine ligand. Reuse of the catalyst after extraction of the product with diethyl ether was possible for at least 6 runs with only a moderate decrease in activity. 

Palladium isocyanide complexes react with amines and alcohols to give palladium Carbene Complexes (equation 15) in a reaction that is a nucleophihc attack on the isonitrile carbon. These complexes easily lose a halide if it is trans to the carbene hgand, since the carbene carbon has a high trans influence. The structures of these compounds have the carbene carbon and its two heteroatom groups in one plane, which is perpendicular to the coordination plane of the Pd. 

As already mentioned for rhodium carbene complexes, proof of the existence of electrophilic metal carbenoids relies on indirect evidence, and insight into the nature of intermediates is obtained mostly through reactivity-selectivity relationships and/or comparison with stable Fischer-type metal carbene complexes. A particularly puzzling point is the relevance of metallacyclobutanes as intermediates in cyclopropane formation. The subject is still a matter of debate in the literature. Even if some metallacyclobutanes have been shown to yield cyclopropanes by reductive elimination [15], the intermediacy of metallacyclobutanes in carbene transfer reactions is in most cases borne out neither by direct observation nor by clear-cut mechanistic studies and such a reaction pathway is probably not a general one. Formation of a metallacyclobu-tane requires coordination both of the olefin and of the carbene to the metal center. In many cases, all available evidence points to direct reaction of the metal carbenes with alkenes without prior olefin coordination. Further, it has been proposed that, at least in the context of rhodium carbenoid insertions into C-H bonds, partial release of free carbenes from metal carbene complexes occurs [16]. Of course this does not exclude the possibility that metallacyclobutanes play a pivotal role in some catalyst systems, especially in copper-and palladium-catalyzed reactions. 

Doyle has put forward arguments against the intermediacy of such complexes in catalytic cyclopropanation . Firstly, metal coordination activates the alkene to nucleophilic attack. Hence, an electrophilic metal carbene would add only reluctantly or not at all. Secondly, the stable PdCl2 complexes of dienes 8 and 428 do not react with ethyl diazoacetate, even if Rh fOAc) or PdCljfPhCbOj is added. The diazoester is decomposed only when it is added to a mixture of the Pd complex and excess diene. These results exclude the metal-carbene-olefin intermediate, but they leave open the possibility of metal carbene interaction with an uncomplexed olefin molecule. The preferred formation of exo-cyclopropanes in the PdCyPhCN) -catalyzed reactions between 8 and N2CHCOOEt or N2CPh2, with exo. endo ratios virtually identical to those observed upon cyclopropanation of monoolefin 429, also rule out coordination of a palladium carbene to the exocyclic double bond of 8 prior to cyclopropanation of the endocyclic double bond. 

Even better results in terms of catalyst recyclability have been obtained in the low viscosity [bmim][NTf2], which plays a dual role as that of the reaction medium and precursor of palladium carbene catalyst (Scheme 1.57). ... 

In 2003, Stoltz at CalTech described a palladium-catalyzed oxidative Wacker cyclization of o-allylphenols such as 55 in nonpolar organic solvents with molecular oxygen to afford dihydrobenzofurans such as 56.44 Interestingly, when (-)-sparteine was used in place of pyridine, dihydrobenzofuran 56 was produced asymmetrically. The ee reached 90% when Ca(OH)2 was added as an additive. Stoltz considered it a stepping stone to asymmetric aerobic cyclizations. In 2004, Mufiiz carried out aerobic, intramolecular Wacker-type cyclization reactions similar to 55—>56 using palladium-carbene catalysts.45 Hiyashi et al. investigated the stereochemistry at the oxypalladation step in the Wacker-type oxidative cyclization of an o-allylphenol. Like o-allylphenol, o-allylbenzoic acid 57 underwent the Wacker-type oxidative cyclization to afford lactone 58.47... 

Recently, palladium complexes of carbene ligands have been recognized as highly reactive catalysts for palladium-promoted reactions, in particular for the Heck reaction [42-44]. The polymer-supported palladium carbene complexes 18 and 19 were prepared by the nucleophilic substitution of the bromomethy-lated Wang resin with 17 under basic reaction conditions (Scheme 7) [45]. The catalytic activity of 18 and 19 was examined for the Heck reaction of aryl bromides with acrylates or styrene to exhibit high TONs up to 5,000. The polymer-supported palladium-carbene complexes are air-stable and recyclable. 

Various bulky phosphines and AT-heterocydic carbene ligands have proved to be effective in a number of palladium-catalyzed reactions of aryl chlorides and bromides [28-30], e.g., Mizoroki-Heck reaction, Suzuki-Miyaura reaction, Migita-Kosugi-Stille reaction, amination, and alkoxylation, as well as the reaction with various carbon nucleophiles as described below. The ligands are considered to enhance both the initial oxidative addition of aryl halides and the reductive elimination of products. The identity of bases is also an important factor to obtain satisfactory results commonly in the arylation of carbon nucleophiles NaH,NaO-t-Bu, K3PO4,M2CO3 (M=K, Cs), and MN(SiMe3)2 (M= Li, Na, K) are typical choices. 

Theoretical density functional calculations on the possibility of addition of imidazolium salts to electron-rich palladium centers predicted an exothermic enthalpy for such a process [36]. These results suggested that, under appropriate reaction conditions and with the use of a proper carbene precursor, this reaction should present a feasible synthetic path to carbene/palladium complexes. Only recently, the addition of the C(2)-H bond of an imidazolium salt, in the form of an ionic liquid, to a Pd(0)/NHC complex with the formation of a stable Pd-H bond has been reported [41]. These complexes bear three carbenes per metal center, the fourth coordination position being occupied by hydrogen. The isolation of these complexes has proven that the beneficial role of ionic liquids as solvent can lead to the formation of catalytically active palladium-carbene complexes (see Scheme 7). 

Not only platinum forms carbene complexes by oxidative addition of 1,3-dialkylimidazolium salts. CaveU and coworkers also reported the formation of stable carbene complexes of nickel and palladium by reaction with imidazolium ionic liquids [53]. Even in cases where the imidazolium was protected with a methyl group in the 2-position of the imidazolium ring, carbene formation has been observed in the 4- or 5-position in some cases [54]. 

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